rs138347314

Positions:

• chr15-100573679-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001040616.3(LINS1):​c.1194A>G​(p.Gln398Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,608,822 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0037 (10 hom.)
• Consequence: LINS1 NM_001040616.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.471

Genes affected

LINS1 (HGNC:30922): (lines homolog 1) The Drosophila segment polarity gene lin encodes a protein, lines, which plays important roles in development of the epidermis and hindgut. This gene encodes a protein containing a lines-like domain. This gene is located on chromosome 15 and clustered with the gene encoding ankyrin repeat and SOCS box-containing protein 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

LINS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 15-100573679-T-C is Benign according to our data. Variant chr15-100573679-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 211378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.471 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00227 (346/152336) while in subpopulation NFE AF= 0.00395 (269/68032). AF 95% confidence interval is 0.00357. There are 0 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LINS1	NM_001040616.3	c.1194A>G	p.Gln398Gln	synonymous_variant	5/7	ENST00000314742.13	NP_001035706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LINS1	ENST00000314742.13	c.1194A>G	p.Gln398Gln	synonymous_variant	5/7	5	NM_001040616.3	ENSP00000318423.8

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00211 AC: 522 AN: 247486 Hom.: 3 AF XY: 0.00228 AC XY: 305 AN XY: 133926

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00132

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.000790

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00366 AC: 5331 AN: 1456486 Hom.: 10 Cov.: 32 AF XY: 0.00363 AC XY: 2627 AN XY: 724616

Gnomad4 AFR exome AF: 0.000453

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.000862

Gnomad4 NFE exome AF: 0.00451

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.00208 AC XY: 155 AN XY: 74494

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00395

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00301 Hom.: 0

Bravo AF: 0.00244

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	LINS1: BP4, BP7, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138347314; hg19: chr15-101113884; COSMIC: COSV100130481; COSMIC: COSV100130481;